This invention relates to novel compositions of matter containing optically pure (-) ketoconazole. These compositions possess potent activity in treating local and systemic fungal, yeast and dermatophyte infections while avoiding adverse effects associated with the administration of the racemic mixture of ketoconazole. Adverse effects include, but are not limited to, hepatotoxicity, arrhythmia, hypersensitivity reactions, including urticaria, nausea, vomiting, abdominal pain, headache, dizziness, and elevations in serum liver enzymes. Also disclosed are methods for treating the foregoing infections in a human while avoiding the adverse effects that are associated with the racemic mixture of ketoconazole by administering the (-) isomer of ketoconazole to said human.
The active compound of these compositions and methods is an optical isomer of ketcoconazole, which is described by Heeres et al., J. Med. Chem. 22, (8), 1003-1005 (1979); Heel et al., Drugs, 23, 1-36, (1982) and in U.S. Pat. Nos. 4,144,346, 4,223,036 and 4,358,449. Chemically, the active compound is the (-) isomer of cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3 -dioxolan-4-yl]methoxy]phenyl]piperazine (I). This isomer will hereinafter be referred to as (-) ketoconazole. ##STR1##
1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3-diox olan-4-yl]methoxy]phenyl]piperazine has two centers of asymmetry and therefore exists as two enantiomeric pairs of diastereomers. Of these, the cis diastereomer is the most active as an antifungal agent. Ketoconazole is available commercially only as the racemic cis diastereomer, (R,S) plus (S,R) in a 1:1 ratio, and the generic name ketoconazole refers to this enantiomeric mixture. The racemic mixture of ketoconazole that is commercially available for administration is a free base, but the pharmacology of salts will be essentially similar.
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985). Thus, solid and broken wedges are used to denote the absolute configuration of a chiral element; wedge outlines and dotted or broken lines (e.g. I) denote enantiomerically pure compounds of indeterminate absolute configuration.
Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L (commonly used only with sugars, amino acids and related compounds) or R and S (universally used) denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (-) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (-) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (-). For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Ketoconazole is an orally active, broad-spectrum anti-fungal agent. The compound, an imidazole derivative structurally related to miconazole and clotrimazole, impairs the synthesis of ergosterol, which is the principal sterol of fungal cell membranes. This presumably results in an increased permeability and leakage of intracellular content. At high concentration, cellular internal organelles involute, peroxisomes increase, and necrotic changes occur.
Following oral administration, ketoconazole provides, at lower doses, a linear increase in serum concentration. The compound is eventually metabolized to several inactive metabolites through oxidation and degradation of the imidazole and piperazine rings, dealkylation, and hydroxylation. While some of a given dose is excreted in the urine, the major route of excretion is via the bile into the intestinal tract [see Brass, C. et al., Antimicro. Agents and Chemotherapy 21, 151-158 (1982); Physicians' Desk Reference 46, 1144-1146 (1992) Medical Economics Co., Inc., Montvale, N.J.].
The racemic mixture of ketoconazole is presently used primarily as an antifungal agent for such systemic infections as candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis, candidiasis, chronic mucocutaneous candidiasis, and oral thrush. The compound is also indicated for severe cutaneous dermatophyte infections in patients who have not responded to topical therapy or oral griseofulvin.
Systemic fungal diseases (systemic mycoses) are usually chronic, very slowly developing conditions induced by opportunistic causative fungi which may not normally be pathogenic. However when they enter a host compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, etc. or by such conditions as emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like, they may become pathogenic. Symptoms in such fungal diseases are generally not intense, and may include fever, chills, anorexia and weight loss, malaise, and depression. Fungal diseases are often confined to typical anatomic distributions, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections when the fungus disseminates from a primary focus. For example, coccidicidomycosis occurs in a primary form as an acute, benign, self-limiting respiratory disease, with progressive disease developing from the primary form as a chronic, often fatal infection of the skin, lymph glands, spleen and liver. Similarly, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Other infectious diseases such as paracoccidioidomycosis and candidiasis offer a different course, and depending on the etiology may exhibit several forms involving the skin, mucous membranes, lymph nodes, and internal organs. The diagnosis of specific fungal diseases may be made by isolation of the causative fungus from sputum, urine, blood, or the bone marrow, or with prevalent fungus types by evidence of tissue invasion.
Superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, hair or nails. The infections may result in a mild inflammation, and cause intermittent remissions and exacerbations of a gradually extending, scaling, raised lesion. Yeast infections including candidiasis, and oral candidiasis (thrush) are usually restricted to the skin, and mucous membranes, and the symptoms vary with the site of infection. Commonly, infections appear as erythematous, often itchy, exudative patches in the axillas, umbilicus, groin, between toes, and on finger-webs. Oral thrush involves an inflamed tongue, or buccal mucosa and presents as white patches of exudate, while chronic mucocutaneous candidiasis is characterized by red, pustular, crusted, thickened lesions on the forehead or nose.
Many of the imidazole antifungal agents, including ketoconazole, share the same adverse effects. These adverse effects include, but are not limited to, nausea, vomiting, anemia, thrombocytosis, hypersensitivity reactions, hepatotoxicity and some central nervous system toxicity. The racemic mixture of ketoconazole has been found to cause nausea and vomiting, anorexia, headache, and dizziness. Hypersensitivity reactions including urticaria, abdominal pain, and hepatotoxicity and elevations in serum liver enzymes are also associated with the administration of the drug. The most common side effects are gastrointestinal, and they occur in 5 to 10% of patients. Hepatoxicity is less common but more serious. Indeed, the use of oral ketoconazole as a first line antifungal is discouraged because of the potentially serious consequences of the low incidence of hepatotoxicity [See, for example, Schaffner Schweiz Med. Wochenschr. 121, 1413-1418 (1991)]. A review article in the British Medical Journal [Lake-Bakaar et al. Brit. Med. J. 294, 419-422 (1987)] reviewed 82 reports, including 5 deaths, of hepatotoxicity associated with ketoconazole therapy during 1981-1984 in the United Kingdom. An analysis of the 75 cases that had been adequately followed up suggested that 16, including 3 deaths, were probably related to treatment with the drug. Of the remainder, 48 were possibly related to treatment. Hepatotoxicity appeared more common in women. The results of serum liver function tests suggested hepatocellular injury in 10 of the 16 probably related cases; the rest showed a mixed pattern. The results of histological examination of the liver often showed evidence of cholestasis. Allergic manifestations such as rash and eosinophilia were rare. Hepatitis was usually reversible when treatment was stopped, with the results of liver function tests returning to normal after an average of 3.1 months. It was concluded that clinical and biochemical monitoring at regular intervals for evidence of hepatitis was advised during long term treatment with racemic ketoconazole to prevent possible serious hepatic injury.
In addition we have found evidence in our own studies in isolated guinea pig hearts that the administration of racemic ketoconazole may be associated with an increased risk of cardiac arrhythmia. Arrhythmia has not been heretofore reported as a side effect of systemic racemic ketoconazole, although a particular subtype of arrhythmia, torsades de pointes, has been reported when racemic ketoconazole was administered concurrently with terfenadine. The lack of clinical reports of arrhythmia or QT anomalies may simply be a reflection of the fact that oral racemic ketoconazole is only indicated as a later resort when other preferred therapies have failed, and thus there is a relatively small subject population.
Thus it would be particularly desirable to find a compound with the advantages of the racemic mixture of ketoconazole which would not have the aforementioned disadvantages.